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Wnt/?-catenin signaling may induce senescence of chondrocytes in osteoarthritis.

ABSTRACT: Osteoarthritis (OA) is an autoimmune disease associated with increasing age. Typically, chondrocyte senescence is believed to serve an important role in the development and progression of OA. However, the specific mechanisms underlying chondrocyte senescence have not been fully addressed. The present study hypothesized that the Wnt/?-catenin signaling may represent a major regulator of chondrocyte senescence. In addition, the acetylated levels of p53 and sirtuin-1 (SIRT-1) were examined as putative markers for chondrocyte senescence, since activation of p53 is considered an important step in the regulation of senescence. The Wnt/?-catenin signaling pathway was activated using LiCl and inhibited using the Wnt signaling pathway inhibitor, dickkopf-1 (DKK1) in order to evaluate the role of this pathway in the development of OA. Senescent cells were detected using the senescence-associated indicator acidic senescence-associated ?-galactosidase (SA-?-gal). The effects of p53 and p16 on chondrocyte senescence were assessed via activation of Wnt/?-catenin signaling using Wnt-1. In addition, ?-catenin was transfected into chondrocytes to induce activation of the Wnt/?-catenin signaling pathway. Finally, a rabbit model of OA was used to assess whether the observed effects on the Wnt/?-catenin signaling pathway and the induction of chondrocyte senescence were perpetuated. Activation of Wnt/?-catenin signaling increased the expression levels of SA-?-gal, p53, p16 and acetylated p53. Transfection of ?-catenin in chondrocytes increased the expression levels of acetylated p53 and decreased the expression levels of SIRT-1, which in turn deacetylated p53 and modulated its activity. Finally, the role of the Wnt/?-catenin signaling pathway was confirmed in the development of OA using a rabbit model with this condition. The present study suggested that activation of the Wnt/?-catenin signaling pathway promoted chondrocyte senescence, through downregulation of SIRT-1 and increased the expression of acetylated p53.

SUBMITTER: Li W

PROVIDER: S-EPMC7401843 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Wnt/β-catenin signaling may induce senescence of chondrocytes in osteoarthritis.

Li Weijun W Xiong Yan Y Chen Weiping W Wu Lidong L

Experimental and therapeutic medicine 20200717 3

Osteoarthritis (OA) is an autoimmune disease associated with increasing age. Typically, chondrocyte senescence is believed to serve an important role in the development and progression of OA. However, the specific mechanisms underlying chondrocyte senescence have not been fully addressed. The present study hypothesized that the Wnt/β-catenin signaling may represent a major regulator of chondrocyte senescence. In addition, the acetylated levels of p53 and sirtuin-1 (SIRT-1) were examined as putat ...[more]

PMID: 32765756

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Project description:BackgroundGEM (GTP-binding protein overexpressed in skeletal muscle) is one of the atypical small GTPase subfamily members recently identified as a regulator of cell differentiation. Abnormal chondrogenesis coupled with an imbalance in the turnover of cartilaginous matrix formation is highly relevant to the onset and progression of osteoarthritis (OA). However, how GEM regulates chondrogenic differentiation remains unexplored.MethodsCartilage tissues were obtained from OA patients and graded according to the ORASI and ICRS grading systems. The expression alteration of GEM was detected in the Grade 4 cartilage compared to Grade 0 and verified in OA mimic culture systems. Next, to investigate the specific function of GEM during these processes, we generated a Gem knockdown (Gem-Kd) system by transfecting siRNA targeting Gem into ATDC5 cells. Acan, Col2a1, Sox9, and Wnt target genes of Gem-Kd ATDC5 cells were detected during induction. The transcriptomic sequencing analysis was performed to investigate the mechanism of GEM regulation. Wnt signaling pathways were verified by real-time PCR and immunoblot analysis. Finally, a rescue model generated by treating Gem-KD ATDC5 cells with a Wnt signaling agonist was established to validate the mechanism identified by RNA sequencing analysis.ResultsA decreased expression of GEM in OA patients' cartilage tissues and OA mimic chondrocytes was observed. While during chondrogenesis differentiation and cartilage matrix formation, the expression of GEM was increased. Gem silencing suppressed chondrogenic differentiation and the expressions of Acan, Col2a1, and Sox9. RNA sequencing analysis revealed that Wnt signaling was downregulated in Gem-Kd cells. Decreased expression of Wnt signaling associated genes and the total β-CATENIN in the nucleus and cytoplasm were observed. The exogenous Wnt activation exhibited reversed effect on Gem loss-of-function cells.ConclusionThese findings collectively validated that GEM functions as a novel regulator mediating chondrogenic differentiation and cartilage matrix formation through Wnt/β-catenin signaling.

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Wnt/?-catenin signaling may induce senescence of chondrocytes in osteoarthritis.

Publications

Wnt/β-catenin signaling may induce senescence of chondrocytes in osteoarthritis.

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